1. Field of the Invention
The present invention relates to a novel selective thrombin inhibitor having the following formula (I): ##STR3## in which R.sup.1 represents acetyl substituted with aryl or aryloxy, or represents sulfonyl substituted with substituted or unsubstituted aryl or N-containing heterocyclic group,
X represents a group of formula ##STR4## R.sup.2 and R.sup.3 independently of one another represent hydrogen; cycloalkyl substituted or unsubstituted with carboxyl or alkoxycarbonyl; arylalkyloxy; hydroxy; or lower alkyl substituted or unsubstituted with carboxyl, alkoxycarbonyl or hydroxy, or PA1 R.sup.2 and R.sup.3 together with nitrogen atom to which they are attached can form a piperidine group substituted with carboxyl or alkoxycarbonyl, PA1 R.sup.4 represents hydrogen, lower alkyl or lower alkoxy, PA1 R.sup.5 represents alkanesulfonyl; alkoxycarbonyl; alkylcarbonyl; formyl; lower alkyl; aryl substituted or unsubstituted with alkoxy or haloalkyl; or hydroxy-substituted lower alkyl, and PA1 R.sup.6 and R.sup.7 independently of one another represent hydrogen, lower alkyl or amino. PA1 R.sup.1 represents acetyl substituted with aryl or aryloxy, or represents sulfonyl substituted with substituted or unsubstituted aryl or N-containing heterocyclic group, PA1 X represents a group of formula ##STR9## R.sup.2 and R.sup.3 independently of one another represent hydrogen; cycloalkyl substituted or unsubstituted with carboxyl or alkoxycarbonyl; arylalkyloxy; hydroxy; or lower alkyl substituted or unsubstituted with carboxyl, alkoxycarbonyl or hydroxy, or PA1 R.sup.2 and R.sup.3 together with nitrogen atom to which they are attached can form a piperidine group substituted with carboxyl or alkoxycarbonyl, PA1 R.sup.4 represents hydrogen, lower alkyl or lower alkoxy, PA1 R.sup.5 represents alkanesulfonyl; alkoxycarbonyl; alkylcarbonyl; formyl; lower alkyl; aryl substituted or unsubstituted with alkoxy or haloalkyl; or hydroxy-substituted lower alkyl, and PA1 R.sup.6 and R.sup.7 independently of one another represent hydrogen, lower alkyl or amino. PA1 R.sup.1 represents acetyl substituted with naphthyl or naphthyloxy, or represents sulfonyl substituted with naphthyl or phenyl which can be substituted or unsubstituted with one to four substituents selected from the group consisting of lower alkyl, lower alkoxy and dialkylamino, PA1 X represents a group of formula ##STR10## R.sup.2 and R.sup.3 independently of one another represent C.sub.3-6 cycloalkyl substituted or unsubstituted with carboxyl or methoxycarbonyl; benzyloxy; lower alkyl substituted or unsubstituted with carboxyl, methoxycarbonyl or hydroxy; or hydroxy, or PA1 R.sup.2 and R.sup.3 together with nitrogen atom to which they are attached can form a piperidine group substituted with carboxyl or methoxycarbonyl, PA1 R.sup.4 represents hydrogen, PA1 R.sup.5 represents methanesulfonyl, ethoxycarbonyl, formyl, ethyl, phenyl, methylcarbonyl, hydroxyethyl, or phenyl which can be substituted or unsubstituted with trifluoromethyl or ethoxy, and PA1 R.sup.6 and R.sup.7 independently of one another represent hydrogen, methyl or amino. PA1 (S)-N-cyclopentyl-N-methyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamin o)propionamide, PA1 (S)-N-butyl-N-methyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)prop ionamide, PA1 (S)-N-cyclopentyl-N-propyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamin o)propionamide, PA1 (S)-N-cyclopentyl-N-(2-benzyloxyethyl)-3-(4-amidrazonophenyl)-2-(2-naphthyl sulfonylamino)propionamide, PA1 (S)-N-cyclopentyl-N-butyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino )propionamide, PA1 (S)-N-cyclopentyl-N-ethyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino )propionamide, PA1 (S)-N-cyclopentyl-N-methyl-3-[4-(methylamidino)phenyl]-2-(2-naphthylsulfony lamino)propionamide, PA1 (S)-N-cyclopentyl-N-methyl-3-[4-(1,1-dimethylamidino)phenyl]-2-(2-naphthyls ulfonylamino)propionamide, PA1 (S)-N-cyclopentyl-N-methyl-3-(4-amidrazonophenyl)-2-[(4-methoxy-2,3,6-trime thylbenzene)sulfonylamino]propionamide, PA1 (S)-N-cyclopentyl-N-hydroxy-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylami no)propionamide, PA1 (S)-N-cyclopentyl-N-(2-hydroxyethyl)-3-(4-amidrazonophenyl)-2-(2-naphthylsu lfonylamino)propionamide, PA1 (S)-N-cyclopentyl-N-methyl-3-[4-(methylamidino)phenyl]-2-[(4-methoxy-2,3,6- trimethylbenzene)sulfonylamino]propionamide, PA1 (S) -N,N-dimethyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino)propionami de, PA1 (S)-N,N-dimethyl-3-[4-(1-methylamidino)phenyl]-2-(2-naphthylsulfonylamino)p ropionamide, PA1 (S)-N-cyclohexyl-N-methyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamino )propionamide, PA1 (S)-N-cyclopropyl-N-methyl-3-(4-amidrazonophenyl)-2-(2-naphthylsulfonylamin o)propionamide, PA1 (S)-3-[4-(amidrazono)-phenyl]-N-cyclopentyl-N-methyl-2-(2-naphthalen-1-yl-a cetylamino)-propionamide, PA1 (S)-3-[4-(amidrazono)-phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylamino-nap hthalene-1-sulfonylamino)-propionamide, PA1 (S)-3-[4-(amidrazono)-phenyl]-N-cyclopentyl-N-methyl-2-(5-methoxy-naphthale ne-1-sulfonylamino)-propionamide, PA1 (S)-2-[4-(amidrazono)-phenyl]-N-cyclopentyl-N-methyl-2-(6,7-dimethoxy-napht halene-2-sulfonylamino)-propionamide, PA1 (S)-3-[4-(methylamidino)-phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylamino- naphthalene-1-sulfonylamino)-propionamide, PA1 (S)-3-[4-(amidrazono)-phenyl]-N-cyclopentyl-N-methyl-2-(naphthalene-1-sulfo nylamino)-propionamide, PA1 (S)-3-[4-(amidrazono)-phenyl]-N-cyclopentyl-N-methyl-2-[2-(naphthalene-1-yl -oxy)acetylamino]-propionamide, PA1 (S)-3-[4-(amidrazono)-phenyl]-N-cyclopentyl-N-methyl-2-[2-(naphthalene-2-yl -oxy)acetylamino]-propionamide, PA1 {[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-me thylamino}-acetic acid methyl ester, PA1 {[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-me thylamino}-acetic acid, PA1 (S)-2-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propion yl]-methylamino}-propionic acid methyl ester, PA1 (S)-2-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propion yl]-methylamino}-propionic acid, PA1 (R)-2-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propion yl]-methylamino}-propionic acid methyl ester, PA1 (R)-2-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propion yl]-methylamino}-propionic acid, PA1 (R)-2-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propion yl]-methylamino}-3-methyl-butyric acid methyl ester, PA1 (R)-2-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propion yl]-methylamino}-3-methyl butyric acid, PA1 3-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]- methylamino}-propionic acid methyl ester, PA1 3-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]- methylamino}-propionic acid, PA1 4-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]- methylamino}-butyric acid methyl ester, PA1 4-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]- methylamino}-butyric acid, PA1 {[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-cy clopropylamino}-acetic acid methyl ester, PA1 {[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-cy clopropylamino}-acetic acid, PA1 {[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-bu tylamino}-acetic acid methyl ester, PA1 {[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-bu tylamino}-acetic acid, PA1 {[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-cy clopentylamino}-acetic acid methyl ester, PA1 {[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-cy clopentylamino}-acetic acid, PA1 1-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]- methylamino}-cyclopentane carboxylic acid methyl ester, PA1 1-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]- methylamino}-cyclopentane carboxylic acid, PA1 2-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]- methylamino}-cyclopentane carboxylic acid ethyl ester, PA1 2-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]- methylamino}-cyclopentane carboxylic acid, PA1 (S)-2-{[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propion yl]-methylamino}-3-methyl-butyric acid methyl ester, PA1 1-[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-p iperidine-(R)-2-carboxylic acid methyl ester, PA1 1-[3-(4-amidrazono-phenyl)-(S)-2-(naphthalene-2-sulfonylamino)-propionyl]-p iperidine-(R)-2-carboxylic acid, PA1 (S)-naphthalene-2-sulfonic acid [1-(4-amidrazono)benzyl-2-(4-methylsulfonyl-piperazinyl)-2-oxoethyl]amide, PA1 (S)-naphthalene-2-sulfonic acid [1-(4-amidrazono)benzyl-2-oxo-2-(4-ethoxycarbonyl-piperazinyl)-ethyl]amide PA1 (S)-naphthalene-2-sulfonic acid [1-(4-amidrazono)benzyl-2-(4-formyl-piperazinyl)-2-oxoethyl]amide, PA1 (S)-naphthalene-2-sulfonic acid [1-(4-amidrazono)benzyl-2-(4-ethyl-piperazinyl)-2-oxoethyl]amide, PA1 (S)-naphthalene-2-sulfonic acid [1-(4-amidrazono)benzyl-2-oxo-2-(4-phenyl-piperazinyl)-ethyl]amide, PA1 (S)-naphthalene-2-sulfonic acid [1-(4-amidrazono)benzyl-2-oxo-2-[4-(3-trifluoromethylphenyl)-piperazinyl)- ethyl]amide, PA1 (S)-naphthalene-2-sulfonic acid [2-(4-acetyl-piperazinyl)-1-(4-amidrazono)benzyl-2-oxoethyl]amide, PA1 (S)-naphthalene-2-sulfonic acid [1-(4-amidrazono)benzyl-2-oxo-2-[4-(2-hydroxyethyl)-piperazinyl]-ethyl]ami de, and PA1 (S)-naphthalene-2-sulfonic acid [1-(4-amidrazono)benzyl-2-oxo-2-4- (2-ethoxyphenyl)-piperazinyl]-ethyl]amide. PA1 X, R.sup.1, R.sup.6 and R.sup.7 are defined as previously described, and PA1 P represents an amino-protecting group.
Some of the compounds of formula (I) can shows an effective thrombin inhibitory activity even through oral administration and therefore, is very valuable.
The present invention also relates to a process for preparing the compound of formula (I) and to a pharmaceutical composition for thrombin inhibition which comprises the compound of formula (I) as an active ingredient.
2. Background Art
It has been generally known that the process for blood coagulation involves numerous complicated enzyme reactions of which the final step includes a reaction of converting prothrombin into thrombin. Thrombin produced from the final step of blood coagulation process activates platelets and converts fibrinogen into fibrin which is then converted into a higher molecular substance by polymerization and cross-linked by the action of activated blood factor XIII to form insoluble blood clotting. Accordingly, thrombin plays an important role in blood coagulation process. Thrombin also activates blood factors V and VIII which in turn accelerates the blood coagulation by a feed-back mechanism.
Thus, since thrombin inhibitors act as effective anti-coagulants and, at the same time, can inhibit the platelet activation and the production and stabilization of fibrin, for a long time, many attempts have been made to find out a method for prevention of blood coagulation and for treatment of various thrombosis using a novel compound which can inhibit thrombin activity.
However, the compound capable of inhibiting only thrombin activity is restricted in use as the effective anti-coagulant and thrombolytic agent. The reason is that since thrombin is one of serine-proteases and numerous serine-proteases similar to trypsin, typically plasmin, are present in human body, particularly in blood, the effective thrombin inhibitor generally also has a high inhibitory activity against such serine-proteases. According to such characteristic feature of thrombin, in development of thrombin inhibitors it is very important that the inhibitor compound has a less inhibitory activity toward a prototype serine protease such as trypsin than thrombin.
Under such conditions, numerous studies have been conducted to develop a selective thrombin inhibitor which can effectively inhibit thrombin and, at the same time, has a little trypsin inhibitory activity. As a result, Argatroban having the following formula (A) as an arylsulfonylarginine-based compound has been developed (see, U.S. Pat. Nos. 4,258,192 and 4,201,863). ##STR5## Argatroban shows a high inhibitory activity for thrombin which is 250 times as high as the activity for trypsin (see, Biochemistry 1984, 23, p85-90). However, it can be obtained only through a complicated synthetic procedure. It has been launched on market in Japan in 1990.
In addition, NAPAP having the following formula (B) as a benzamidine-based arylsulfonyl compound has also been developed. ##STR6## This compound can be readily synthesized and has an effective thrombin inhibitory activity. However, it has a disadvantage in that the thrombin inhibitory activity is merely 50 times as high as the activity for trypsin (see, J. Biol. Chem. 1991, 266, p20085-20093).
Further, Ro 46-6240 having the following formula (C) has been reported as the compound having an improved selectivity for thrombin over trypsin. This compound shows a possibility of development as an intravenous injectable formulation due to its short half-life in blood, but does not show any possibility for oral administration (see, J. Med. Chem. 1994, 37, 3889-3901). ##STR7##
In addition, a piperazide-based compound as recently developed has been reported as having somewhat possibility for oral administration in rat but having a low selectivity for thrombin (see WO 94/18185). Thus, such compounds did not come up to the expectation in this art.
Therefore, the present inventors have extensively studied to develop a certain compound which can be easily synthesized, shows an effective thrombin inhibitory activity with a high selectivity for thrombin over trypsin and can also be administered via oral route. As a result, we have identified that the thrombin inhibitor of formula (I) according to the present invention can achieve such purpose and thus completed the present invention.
Accordingly, it is an object of the present invention to provide a novel thrombin inhibitor of formula (I), as defined above, which can be administered via oral route and has a high selectivity for thrombin.
It is another object of the present invention to provide a process for preparing the thrombin inhibitor of formula (I).
Further, it is still another object of the present invention to provide a pharmaceutical composition for prevention of blood coagulation and treatment of various thrombosis, which comprises the thrombin inhibitor of formula (I) as an active ingredient.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the disclosure of invention, in addition to the scope of the invention defined by the claims.